ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma
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eLife assessment
Here, Morgan and colleagues report a novel synthetic lethal interaction between nucleoporin inhibition and KRAS-driven hepatocyte hyperproliferation. The authors show that nucleoporin inhibitor treatment or heterozygosity of nucleoporin genes (ahctf1 and/or ranbp2) suppresses KRAS-driven zebrafish larval liver overgrowth, providing impetus for developing Nup inhibitors as hepatocellular carcinoma treatment. Their data provide insights into the consequences of nucleoporin inhibition in cancer, demonstrating that disrupting ahctf1 decreases proliferation and promotes apoptosis by impairing nuclear pore formation and mitotic spindle assembly through a mechanism that may be at least partially dependent on tp53.
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Abstract
The nucleoporin (NUP) ELYS, encoded by AHCTF1 , is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene ( kras G12V ) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks kras G12V -driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the 10 components of the NUP107–160 subcomplex, which includes AHCTF1 , is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.
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Author Response
Reviewer #1 (Public Review):
This paper shows that nuclear pore complex components are required for Kras/p53 driven liver tumors in zebrafish. The authors previously found that nonsense mutation in ahctf1 disrupted nuclear pore formation and caused cell death in highly proliferative cells in vivo. In the absence of this gene, there are multiple mitotic functions involving the nuclear pore that are defective, leading to p53 dependent cell death. Heterozygous fish are viable but have reduced kras/p53 liver tumor growth, and this is associated with multiple nuclear and mitotic defects that lead to cancer cell death/lack of growth. This therapeutic window suggests targetability of this pathway in cancer. I think the data are robust, rigorous, and clearly presented. I believe this in vivo work will encourage therapeutic …
Author Response
Reviewer #1 (Public Review):
This paper shows that nuclear pore complex components are required for Kras/p53 driven liver tumors in zebrafish. The authors previously found that nonsense mutation in ahctf1 disrupted nuclear pore formation and caused cell death in highly proliferative cells in vivo. In the absence of this gene, there are multiple mitotic functions involving the nuclear pore that are defective, leading to p53 dependent cell death. Heterozygous fish are viable but have reduced kras/p53 liver tumor growth, and this is associated with multiple nuclear and mitotic defects that lead to cancer cell death/lack of growth. This therapeutic window suggests targetability of this pathway in cancer. I think the data are robust, rigorous, and clearly presented. I believe this in vivo work will encourage therapeutic targeting of NPCs in cancer.
We are pleased that this reviewer believes that our data are robust, rigorous, and clearly presented and that our in vivo work will encourage therapeutic targeting of NPCs in cancer.
Reviewer #2 (Public Review):
Overall this is a very interesting and important paper that demonstrates a novel synthetic interaction between nucleoporin inhibition and oncogene-driven hyperproliferation. This work is especially significant because of the paucity of effective treatments for hepatocellular carcinoma (HCC). The authors' demonstration that the Nup inhibitor Selinexor decreases larval liver size in KRAS-overexpressing zebrafish but does not cause toxicity in wild-type animals lays the groundwork for exploiting this class of drugs in HCC treatment. This paper represents an elegant demonstration of the utility of zebrafish models in cancer studies. The relevance of this work to human cancer is supported by the authors' studies using TCGA data, wherein they demonstrate that decreased NUP expression is associated with increased survival in HCC.
Other major strengths of the paper include beautiful pictures demonstrating that ahctf1+/- decreases the density and volume of nuclear pores in TO(kras) larvae and increases the rate of multipolar spindle formation, misaligned chromosomes, and anaphase bridges. The experiments are very well-controlled, including detailed analysis of the effects of ahctf1 heterozygosity and Selinexor on wild-type animals. The inclusion of distinct methods for disruption nucleoporins (ranbp2 heterozygosity and drug treatment) bolsters the authors' conclusion that this represents a viable drug target in HCC.
My major concerns are as follows:
- The authors state that "the beneficial effect of ahctf1 heterozygosity to reduce tumour burden persists in the absence of functional Tp53, due to compensatory increases in the levels of tp63 and tp73". However, tp63 and tp73 appear similarly upregulated in ahctf1 heterozygotes regardless of tp53 status. The authors do not provide enough evidence that tp63 and tp73 are compensating for tp53 loss. An alternative possibility based on the data presented is that the effects of ahctf1+/- are independent of tp53 family members, and the effects on apoptosis go through a different pathway.
We agree with this reviewer that we did not provide enough evidence that tp63 and tp73 are compensating for tp53 loss. Accordingly, we have addressed this issue comprehensively.
- The authors state in multiple locations that nucleoporin inhibition decreases tumor burden. In my opinion, this is not strictly correct. The TO(kras) model clearly results in HCC in adults, but it's a little unclear whether the larval liver overgrowth is truly HCC or not based on the original paper by Nguyen et al. (2012 Dis Model Mech).
We agree with these comments and accordingly, we performed several new experiments in adult fish.
Reviewer #3 (Public Review):
The nuclear transport machinery is aberrantly regulated in many cancers in a context-dependent fashion, and mounting evidence with cultured cell and animal models indicates that reducing the activity or expression of certain nuclear transport proteins can selectively kill cancer cells while sparing nontransformed cells. Here the authors further explore this concept using a zebrafish model for hepatocellular carcinoma (HCC) induced by liver-specific transgenic expression of oncogenic krasG12V. The transgene causes greatly increased liver size by day 7 in larvae, associated with a gene expression profile that resembles early-stage human HCC. This study focuses on Ahctf1, a nuclear pore complex (NPC) protein known to be essential for postmitotic NPC assembly. Using the krasG12V background, the authors analyze animals that are heterozygous for a recessive mutation in the ahctf1 gene that leads to ~50% reduction in ahctf1 mRNA (and likely the encoded protein). The authors show that the ~4-fold increase in liver volume of krasG12V animals is reduced by ~1/3 in the ahctf1 heterozygous mutants. This is associated with increased apoptosis, decreased DNA replication, up-regulation of pro-apoptotic and cdk-inhibitor genes, and down-regulation of anti-apoptotic gene. These effects found to be substantially Tp53-dependent. Consistent with previous Ahctf1 depletion studies, hepatocytes of ahctf1 heterozygotes show decreased NPC density at the nuclear surface, elevated levels of aberrant mitoses and increased DNA damage/double stranded breaks. Finally, the authors show that combining the achtf1 heterozygous mutant with a heterozygous mutation in another NPC protein- RanBP2- or treating animals with a chemical inhibitor of exportin-1 (Selinexor) can further reduce liver volume. Overall they suggest that combinatorial targeting of the nuclear transport machinery can provide a therapeutic approach for targeting HCC.
This is an interesting study that bolsters the notion that reduction in the levels of discrete nucleoporins (and/or inhibiting specific nuclear transport pathways) can result in cancer cell-selective killing. Moreover, the work extends previous studies involving cultured cell and mouse xenografts to a new cancer model (HCC) and nucleoporin (Ahctf1). Whereas the authors describe multiple aberrant cellular phenotypes associated with the dosage reduction in ahctf1, the exact causes for reduction in liver size in the krasG12V model remain unclear. Although it would be desirable to parse effects of Ahctf1 related to NPC number, aberrant mitoses, licensing of DNA replication and chromatin regulation, this is a tall order at present, given the limited understanding of Ahctf1. However, useful insight on these and related questions could be gained with further analysis of the system as outlined below.
We are pleased this reviewer thinks this is an interesting study that bolsters the notion that reduction in the levels of discrete nucleoporins (and/or inhibiting specific nuclear transport pathways) can result in cancer cell-selective killing. This reviewer also suggests that useful insight on these and related questions could be gained with further analysis of the system as outlined below:
- In the krasG12V model, it would be helpful to distinguish the contribution of increased cell death vs decreased cell proliferation to the change in liver size seen with heterozygous ahctf1. Is this predominantly due to decreased proliferation?
We think this question is difficult to address, because the relative contributions of the two processes may vary with time. Our data show definitively that by 7 dpf, the impact of ahctf1 heterozygous mutation has disrupted multiple cellular processes, leading to a 40% increase in the number of hepatocytes expressing Annexin 5 (dying cells), and a 40% decrease in the number of hepatocytes incorporating EdU over a 2 h incubation (fewer cells in S-phase). Both responses are likely to contribute to the reduction in liver volume observed in response to ahctf1 heterozygosity. It is worth stating that in our experiments, we captured snapshots of apoptosis and DNA replication in the livers of larvae at 7 days post-fertilisation after 5d of dox treatment/KrasG12V expression. To answer the Reviewer’s question properly, we would need to monitor the behaviour of individual cells over time. If such experiments were technically possible, we think that some cells that undergo growth arrest in response to dox treatment might ultimately succumb to apoptosis (unless dox treatment is withdrawn) while other cells might enter into a state of prolonged senescence. However, given the technical challenges, we did not attempt to test this in the current manuscript.
- It would be good to know whether the heterozygous ahctf1 state blunts the overall level of Ras activity in krasG12V animals.
We have addressed this interesting question thoroughly in new Fig. 1g, h. To do this, we used a commercial RAS-RBD pulldown kit followed by western blot analysis to determine the levels of activated GTP-bound Kras protein. Our results demonstrate that the levels of GTP-bound Kras protein, expressed as a proportion of total Kras protein, do not change in response to ahctf1 heterozygosity. We conclude from these data that the potentially therapeutic value of reduced ahctf1 expression in a cancer setting is not caused by inhibiting Kras activity.
- Notwithstanding the analysis of Tp53 target genes presented in this study, it would be helpful to see detailed transcriptional profiling of hepatocytes in the krasG12V model with the heterozygous ahctf1 mutation, and to assess the effects of Selinexor. GSEA type analysis offers a way to start untangling the effects of these pathways. Moreover this analysis could provide insight on the relevance of this model to human HCC.
We used RNAseq to address the relevance of our larval model to human HCC. Specifically, we performed differential gene expression analysis to identify up- and downregulated genes in cohorts of ahctf1+/+ (WT) larvae versus dox-treated ahctf1+/+(WT);krasG12V larvae. We used gene set enrichment analysis to compare these differentially regulated transcripts with the gene expression signature of 369 patient samples in the Liver hepatocellular carcinoma (LIHC) dataset versus healthy liver samples in the TCGA. These analyses revealed a significant association between the patterns of gene expression in our larval model of zebrafish HCC and those of human HCC (Fig. 1-figure supplement 1c, d).
The genetic experiments we report in Figures 4, 5, 6 show that WT Tp53 is required for the reductions in liver enlargement (Fig. 4), apoptosis (Fig. 5) and DNA replication (Fig. 6) that occurs in response to ahctf1 heterozygosity in dox-treated krasG12V larvae. We also used RT-qPCR to show that a Tp53-mediated transcriptional program was activated in these ahctf1 heterozygous livers (Fig. 5). Similarly, in adult livers, ahctf1 heterozygosity triggered the upregulation of Tp53 target genes, including pro-apoptotic genes (pmaip1, bbc3, bim and bax) and cell cycle arrest genes (cdkn1a and ccng1) (new Fig. 6-figure supplement 1). These results show that to obtain the full potential of ahctf1 heterozygosity in reducing growth and survival of KrasG12V-expressing hyperplastic hepatocytes requires activation of WT Tp53. This is an important conclusion from our paper that is likely to be relevant in a clinical setting, for instance in patient selection, if ELYS inhibitors are developed for the treatment of HCC in which the KRAS/MAPK pathway is activated.
Also, one reviewer mentions performing genome-wide transcriptional profiling of hepatocytes in the krasG12V model in response to ahctf1 heterozygosity and the presence and absence of Selinexor treatment. While these are potentially interesting experiments, they are substantial in nature and not crucial for the main messages of our paper. Therefore, we respectively contend that they are beyond the scope of the current manuscript.
- Functions of Achtf1 in regard to chromatin regulation could be compromised in this model. Scholz et al (Nat Gen 2019) report that Ahctf1 is involved in increasing Myc expression via gene gating mechanism. It would be good to know what the effects are in this system.
The Scholz, 2019 and Gondor, 2022 papers from the same group, are very interesting in that they demonstrate a novel role for the ELYS protein in addition to the ones we pursued in our paper. The authors showed that in HCT116 cells, a human colorectal cancer cell line in which proliferation is driven by aberrant WNT/CTNNB1 signalling, the longevity of nascent MYC mRNA was increased by accelerating its movement from the nucleus to the cytoplasm, thereby preventing its degradation by nuclear surveillance mechanisms. The authors showed that siRNA knockdown of AHCTF1 in HCT-116 cells reduced the rate of nuclear export of MYC transcripts without changing the transcriptional rate of the MYC gene. They proposed a mechanism that depended on the formation of a complex chromatin architecture comprising transcriptionally active MYC and CCAT1 alleles plus proteins including β-Catenin, CTCF and ELYS. Together these interacting components guided nascent MYC mRNA molecules to nuclear pores, enhanced their export to the cytoplasm to be translated, resulting in activation of a MYC transcriptional program that induced expression of pro-proliferation genes.
In theory, this role of ELYS in protecting MYC from nuclear degradation might extrapolate to other cancer settings where MYC expression is elevated. While interplay between MYC and mutant KRAS to enhance cancer growth has been previously reported, to date, most emphasis on this interaction has focused on the role of mutant KRAS in increasing the stability of the MYC protein, for example via RAS effector protein kinases (ERK1/2 and ERK5) that stabilise MYC by phosphorylation at S62 (Farrell and Sears, 2014: https://doi.org/10.1101/cshperspect.a014365) (Vaseva and Blake 2018: DOI:https://doi.org/10.1016/j.ccell.2018.10.001). While we appreciate the novelty of the recent papers, the current findings are limited to -Catenin activated HCT-116 cells and may not be relevant to our zebrafish model of mutant Kras-driven HCC. Accordingly, we have not allocated a high priority to following this up in our current manuscript.
- The synthetic lethality argument pressed in this manuscript seems exaggerated. Standard anti-cancer treatments typically target several cellular pathways, and nucleoporins directly affect a multiplicity of pathways besides nuclear transport.
While we do not disagree that standard anti-cancer treatments may target several cellular pathways, we believe our data are consistent with the accepted definition of a synthetic lethal interaction whereby single mutations in two separate genes (kras and ahctf1) cooperate to cause cell death, whereas cells harbouring just one of these mutations are spared.
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eLife assessment
Here, Morgan and colleagues report a novel synthetic lethal interaction between nucleoporin inhibition and KRAS-driven hepatocyte hyperproliferation. The authors show that nucleoporin inhibitor treatment or heterozygosity of nucleoporin genes (ahctf1 and/or ranbp2) suppresses KRAS-driven zebrafish larval liver overgrowth, providing impetus for developing Nup inhibitors as hepatocellular carcinoma treatment. Their data provide insights into the consequences of nucleoporin inhibition in cancer, demonstrating that disrupting ahctf1 decreases proliferation and promotes apoptosis by impairing nuclear pore formation and mitotic spindle assembly through a mechanism that may be at least partially dependent on tp53.
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Reviewer #1 (Public Review):
This paper shows that nuclear pore complex components are required for Kras/p53 driven liver tumors in zebrafish. The authors previously found that nonsense mutation in ahctf1 disrupted nuclear pore formation and caused cell death in highly proliferative cells in vivo. In the absence of this gene, there are multiple mitotic functions involving the nuclear pore that are defective, leading to p53 dependent cell death. Heterozygous fish are viable but have reduced kras/p53 liver tumor growth, and this is associated with multiple nuclear and mitotic defects that lead to cancer cell death/lack of growth. This therapeutic window suggests targetability of this pathway in cancer. I think the data are robust, rigorous, and clearly presented. I believe this in vivo work will encourage therapeutic targeting of NPCs in …
Reviewer #1 (Public Review):
This paper shows that nuclear pore complex components are required for Kras/p53 driven liver tumors in zebrafish. The authors previously found that nonsense mutation in ahctf1 disrupted nuclear pore formation and caused cell death in highly proliferative cells in vivo. In the absence of this gene, there are multiple mitotic functions involving the nuclear pore that are defective, leading to p53 dependent cell death. Heterozygous fish are viable but have reduced kras/p53 liver tumor growth, and this is associated with multiple nuclear and mitotic defects that lead to cancer cell death/lack of growth. This therapeutic window suggests targetability of this pathway in cancer. I think the data are robust, rigorous, and clearly presented. I believe this in vivo work will encourage therapeutic targeting of NPCs in cancer.
-
Reviewer #2 (Public Review):
Overall this is a very interesting and important paper that demonstrates a novel synthetic interaction between nucleoporin inhibition and oncogene-driven hyperproliferation. This work is especially significant because of the paucity of effective treatments for hepatocellular carcinoma (HCC). The authors' demonstration that the Nup inhibitor Selinexor decreases larval liver size in KRAS-overexpressing zebrafish but does not cause toxicity in wild-type animals lays the groundwork for exploiting this class of drugs in HCC treatment. This paper represents an elegant demonstration of the utility of zebrafish models in cancer studies. The relevance of this work to human cancer is supported by the authors' studies using TCGA data, wherein they demonstrate that decreased NUP expression is associated with increased …
Reviewer #2 (Public Review):
Overall this is a very interesting and important paper that demonstrates a novel synthetic interaction between nucleoporin inhibition and oncogene-driven hyperproliferation. This work is especially significant because of the paucity of effective treatments for hepatocellular carcinoma (HCC). The authors' demonstration that the Nup inhibitor Selinexor decreases larval liver size in KRAS-overexpressing zebrafish but does not cause toxicity in wild-type animals lays the groundwork for exploiting this class of drugs in HCC treatment. This paper represents an elegant demonstration of the utility of zebrafish models in cancer studies. The relevance of this work to human cancer is supported by the authors' studies using TCGA data, wherein they demonstrate that decreased NUP expression is associated with increased survival in HCC.
Other major strengths of the paper include beautiful pictures demonstrating that ahctf1+/- decreases the density and volume of nuclear pores in TO(kras) larvae and increases the rate of multipolar spindle formation, misaligned chromosomes, and anaphase bridges. The experiments are very well-controlled, including detailed analysis of the effects of ahctf1 heterozygosity and Selinexor on wild-type animals. The inclusion of distinct methods for disruption nucleoporins (ranbp2 heterozygosity and drug treatment) bolsters the authors' conclusion that this represents a viable drug target in HCC.My major concerns are as follows:
1. The authors state that "the beneficial effect of ahctf1 heterozygosity to reduce tumour burden persists in the absence of functional Tp53, due to compensatory increases in the levels of tp63 and tp73". However, tp63 and tp73 appear similarly upregulated in ahctf1 heterozygotes regardless of tp53 status. The authors do not provide enough evidence that tp63 and tp73 are compensating for tp53 loss. An alternative possibility based on the data presented is that the effects of ahctf1+/- are independent of tp53 family members, and the effects on apoptosis go through a different pathway.
2. The authors state in multiple locations that nucleoporin inhibition decreases tumor burden. In my opinion, this is not strictly correct. The TO(kras) model clearly results in HCC in adults, but it's a little unclear whether the larval liver overgrowth is truly HCC or not based on the original paper by Nguyen et al. (2012 Dis Model Mech).
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Reviewer #3 (Public Review):
The nuclear transport machinery is aberrantly regulated in many cancers in a context-dependent fashion, and mounting evidence with cultured cell and animal models indicates that reducing the activity or expression of certain nuclear transport proteins can selectively kill cancer cells while sparing nontransformed cells. Here the authors further explore this concept using a zebrafish model for hepatocellular carcinoma (HCC) induced by liver-specific transgenic expression of oncogenic krasG12V. The transgene causes greatly increased liver size by day 7 in larvae, associated with a gene expression profile that resembles early-stage human HCC. This study focuses on Ahctf1, a nuclear pore complex (NPC) protein known to be essential for postmitotic NPC assembly. Using the krasG12V background, the authors analyze …
Reviewer #3 (Public Review):
The nuclear transport machinery is aberrantly regulated in many cancers in a context-dependent fashion, and mounting evidence with cultured cell and animal models indicates that reducing the activity or expression of certain nuclear transport proteins can selectively kill cancer cells while sparing nontransformed cells. Here the authors further explore this concept using a zebrafish model for hepatocellular carcinoma (HCC) induced by liver-specific transgenic expression of oncogenic krasG12V. The transgene causes greatly increased liver size by day 7 in larvae, associated with a gene expression profile that resembles early-stage human HCC. This study focuses on Ahctf1, a nuclear pore complex (NPC) protein known to be essential for postmitotic NPC assembly. Using the krasG12V background, the authors analyze animals that are heterozygous for a recessive mutation in the ahctf1 gene that leads to ~50% reduction in ahctf1 mRNA (and likely the encoded protein). The authors show that the ~4-fold increase in liver volume of krasG12V animals is reduced by ~1/3 in the ahctf1 heterozygous mutants. This is associated with increased apoptosis, decreased DNA replication, up-regulation of pro-apoptotic and cdk-inhibitor genes, and down-regulation of anti-apoptotic gene. These effects found to be substantially Tp53-dependent. Consistent with previous Ahctf1 depletion studies, hepatocytes of ahctf1 heterozygotes show decreased NPC density at the nuclear surface, elevated levels of aberrant mitoses and increased DNA damage/double stranded breaks. Finally, the authors show that combining the achtf1 heterozygous mutant with a heterozygous mutation in another NPC protein- RanBP2- or treating animals with a chemical inhibitor of exportin-1 (Selinexor) can further reduce liver volume. Overall they suggest that combinatorial targeting of the nuclear transport machinery can provide a therapeutic approach for targeting HCC.
This is an interesting study that bolsters the notion that reduction in the levels of discrete nucleoporins (and/or inhibiting specific nuclear transport pathways) can result in cancer cell-selective killing. Moreover, the work extends previous studies involving cultured cell and mouse xenografts to a new cancer model (HCC) and nucleoporin (Ahctf1). Whereas the authors describe multiple aberrant cellular phenotypes associated with the dosage reduction in ahctf1, the exact causes for reduction in liver size in the krasG12V model remain unclear. Although it would be desirable to parse effects of Ahctf1 related to NPC number, aberrant mitoses, licensing of DNA replication and chromatin regulation, this is a tall order at present, given the limited understanding of Ahctf1. However, useful insight on these and related questions could be gained with further analysis of the system as outlined below.
In the krasG12V model, it would be helpful to distinguish the contribution of increased cell death vs decreased cell proliferation to the change in liver size seen with heterozygous ahctf1. Is this predominantly due to decreased proliferation?
It would be good to know whether the heterozygous ahctf1 state blunts the overall level of Ras activity in krasG12V animals.
Notwithstanding the analysis of Tp53 target genes presented in this study, it would be helpful to see detailed transcriptional profiling of hepatocytes in the krasG12V model with the heterozygous ahctf1 mutation, and to assess the effects of Selinexor. GSEA type analysis offers a way to start untangling the effects of these pathways. Moreover this analysis could provide insight on the relevance of this model to human HCC.
Functions of Achtf1 in regard to chromatin regulation could be compromised in this model. Scholz et al (Nat Gen 2019) report that Ahctf1 is involved in increasing Myc expression via gene gating mechanism. It would be good to know what the effects are in this system. Indeed, anti-cancer effects from depletion of Nup93 in a breast cancer model was reported to involve a role of Nup93 in chromatin regulation (Bersini et al, Life Sci Alliance 2020).
If feasible, it would be important to know if loss/reduction in Tp63, proposed to compensate with Tp53 loss, would alter the effects of Achtf1 depletion.
The synthetic lethality argument pressed in this manuscript seems exaggerated. Standard anti-cancer treatments typically target several cellular pathways, and nucleoporins directly affect a multiplicity of pathways besides nuclear transport.
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